Is GHR p.Phe276Ser (c.827T>C) pathogenic?

GHR p.Phe276Ser (c.827T>C) is classified Uncertain significance in GHR (ClinVar, Single submitter, 1 submitter; last evaluated 2024-12-24). AlphaMissense: likely benign (0.097); Very rare (popmax 0.00137%, afr); Associated with Inborn genetic diseases.

What condition is associated with GHR p.Phe276Ser (c.827T>C)?

GHR p.Phe276Ser (c.827T>C) is associated with Inborn genetic diseases (ClinVar).

How common is GHR p.Phe276Ser (c.827T>C) in the general population?

GHR p.Phe276Ser (c.827T>C) is very rare (popmax 0.00137%, afr) (gnomAD).

What do computational predictors say about GHR p.Phe276Ser (c.827T>C)?

AlphaMissense predicts likely benign (score 0.097) — an in-silico prediction, not a clinical call.

GHR p.Phe276Ser

c.827T>C · VCV3853938

Uncertain significance Single submitter

Classification

Uncertain significance

ClinVar

Review

Single submitter ★☆☆☆

ClinVar · 1 submitter

AlphaMissense

likely benign

0.097 · ACMG-weighted

gnomAD v4.1

Rare

very rare (popmax 0.00137%, afr)

Missense predictors

0/2 damaging

AlphaMissense, SaProt · REVEL indeterminate

Conditions

Inborn genetic diseases

Computational evidence

Protein change
AlphaMissense	0.097	likely benign
REVEL	0.366	indeterminate
SaProt	LLR -6.22	tolerated
⇒ AlphaMissense and SaProt both call this tolerated; REVEL is indeterminate.
Splicing
SpliceAI	—	not assessed · no allele here is in the release
Constraint at this position
Conservation	phyloP 0.32	GERP -3.2, phastCons 1
Regional constraint	o/e 1.04	unconstrained · MANE · 154 kb · p 0.32 · regional, not allelic
Overall
CADD	17.43	PHRED · no single calibrated threshold — expert panels disagree

ClinVar classifies this uncertain; the computational predictors unanimously lean tolerated — a triage signal, not a reclassification

AlphaMissense carries the ACMG weight for missense; REVEL and SaProt are independent agreement signals.

Population frequency

gnomAD v4.1 · exomes + genomes

Grpmax group 0.00137% African / African-American · 1/72,806 alleles

Overall 0.000133% 2/1,507,896 alleles · very rare exomes 1/1,355,674 · genomes 1/152,222 · joint denominator

Ancestry group	Frequency	1 in
African / African-Americangrpmax	0.00137%	72,806
European (non-Finnish)	9.2e-05%	1,086,420

Rarity supports pathogenicity (ACMG PM2); frequency above a disease-specific BA1/BS1 threshold argues against it. A variant frequent in one ancestry group can be near-absent in others, so a single global figure can mislead.

Variant & gene context

Gene: GHR
Protein: p.Phe276Ser
Coding: c.827T>C
MANE Select: NM_000163
Type: single nucleotide variant
Location: chr5:42713471 (GRCh38)
Gene constraint: LOEUF 0.65 · pLI 0.16 (gnomAD)
Structure: AlphaFold pLDDT 59.70 · 11 PDB
Residue 276: an α-helix

Full GHR gene report on Sugi Atlas → Gene function, pathways, protein structure, interactions & more

Disease context

Inborn genetic diseases — disease report on Sugi Atlas → Associated genes, phenotypes, clinical trials & treatments

Similar variants

GHR p.Phe276Leu Uncertain significance ★ ⚠ same residue
GHR p.Ala401Gly Uncertain significance ★★ ⚠ same condition
GHR p.Ala421Glu Uncertain significance ★★ ⚠ same condition
GHR p.Arg386His Uncertain significance ★★ ⚠ same condition
GHR p.Arg57His Uncertain significance ★★ ⚠ same condition
GHR p.Asn402Ile Uncertain significance ★★ ⚠ same condition
GHR p.Asp137His Uncertain significance ★★ ⚠ same condition
GHR p.Asp354Val Uncertain significance ★★ ⚠ same condition

Built on 18 open, versioned datasets — ClinVar, gnomAD, AlphaMissense, REVEL, ClinGen & more — plus Sugi Variant's own cross-source analysis. Source data 2026-01–2026-10, ClinVar 2026-10. Full sources & versions →

Cite Sugi Variant

Gür T. Sugi Variant: A Deterministic Per-Variant Germline Reference from a Knowledge Graph for Humans and AI Agents. 2026. doi:10.5281/zenodo.21509445. This variant: https://sugi.bio/variant/ghr-p-phe276ser (accessed [today's date]).

Preprint & method: sugi.bio/variant/method Machine-readable: this page as Markdown